EP2800471A1 - Complexe métalliques de poly (carboxyl) amine contenant des ligands ayant une affinité pour l'anhydrase carbonique ix - Google Patents

Complexe métalliques de poly (carboxyl) amine contenant des ligands ayant une affinité pour l'anhydrase carbonique ix

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Publication number
EP2800471A1
EP2800471A1 EP13733617.8A EP13733617A EP2800471A1 EP 2800471 A1 EP2800471 A1 EP 2800471A1 EP 13733617 A EP13733617 A EP 13733617A EP 2800471 A1 EP2800471 A1 EP 2800471A1
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European Patent Office
Prior art keywords
group
bis
compound
metal complex
alkyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP13733617.8A
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German (de)
English (en)
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EP2800471A4 (fr
Inventor
John W BABIC
Craig Zimmerman
John Joyal
Shawn Lu
Shawn HILLIGER
Kevin P MARESCA
John Marquis
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Molecular Insight Pharmaceuticals Inc
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Molecular Insight Pharmaceuticals Inc
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Publication of EP2800471A1 publication Critical patent/EP2800471A1/fr
Publication of EP2800471A4 publication Critical patent/EP2800471A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings

Definitions

  • the present technology relates generally to the field of radiopharmaceuticals and their use in nuclear medicine for the treatment of various disease states. It is well known that tumors may express unique proteins associated with their malignant phenotype or may over- express normal const ituent proteins as compared to the expression of these proteins in normal cells. The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose, characterize ad treat disease conditions by using radiopharmaceutical compounds that selectively bind to specific tumor cell surface proteins. In particular, the present inventors have found that radiolabeled ligands that specifically bind to the CA-IX isoform of the enzyme carbonic anhydrase. often over-expressed on many cancer cells provides an attractive route for non-invasive and selective treatment of cancers.
  • CA-IX is a membrane-anchored, its catalytic domain resides in the extracellular space. It has a limited tissue distribution and is found at low levels primarily in the gastrointestinal tract.
  • the expression of CA-IX is under the control of H IF- 1 ct, and this isozyme is highly expressed in tumors cells exposed to hypoxia both in vitro and in vivo. Increased CA-IX expression has been detected in carcinomas of the cervix, ovary, kidney, esophagus, lung, breast, and brain.
  • radionuclides are known to be useful for radioimaging and radiotherapy, including Re- 1 86, Re- 1 88, Tc-99m, Ga-67, In- I l l , 1- 123, and 1- 13 1.
  • the present invention provides bi unctional molecules that comprise a specific receptor honing bioactive molecule covalently tethered to Pt, M Cu, I N6 Re, 1 KS Rc, or w "Tc as tumor-selective imaging agents.
  • the present invention is directed to certain poly(carboxyl)amine-containing ligands described herein and their metal complexes.
  • the poly(carboxyl)amine- containing ligands conform to compounds according to Formula I, or a pharmaceutically acceptable salt, tautomer, or ester thereof.
  • X in Formula I is selected from the group consisting of -(CH 2 ) n -, -(CFI 2 ) n -0-, - (CH 2 ) n -N(R g )-, -(CH 2 ) n -N(R g )-C(0)- and -0-.
  • Substituent R g is hydrogen or (Ci-C 6 )alkyl, while A, B and D are each independently -(CH)-, or -N-.
  • E is -(CH 2 )-Z-Q
  • E' is -(CH 2 )-Z-Q'
  • Z is -(CH 2 ) P -, or -C(O)-.
  • Group Q is selected from the group consisting of -H, -OR g , and NR a R b while Q' is selected from the group consisting of -H, -OR g , and R d R e -
  • Subtituent groups R a , R b Rj and R e are each independently hydrogen, (Ci-C 6 )alkyl, or carboxy(C C 6 )alkylene.
  • G is -(CH(R m )) n -R h -, or -(CH 2 ) p -C(0)-R h , and R h is selected from the group consisting of -H, -OH, NR a R b and -C0 2 H.
  • R m in Formula I compounds is selected from the group consisting of -H, -COOH and ⁇ COO(C i -C 1 6)alkyl while subscripts m, n and p independently are integers between 0 to 10 inclusive.
  • any alkyl or carboxyalkyl is optionally substituted with one or more members selected from the group consisting of hydrogen, carboxy(Ci -C 6 )alkylene, hydroxy((' i -C ( ,)alkylenc and amino(C i -C 6 )alkyIene;
  • substituent groups R a and R b are each independently
  • R a and R d are each independently hydrogen, and R h and R c (C
  • R a and Ra are each independently hydrogen
  • -C(,)alkyl for example, an alkyl group that is further substituted with carboxyalkylene groups.
  • Exemplary of such a Formula I compound is one in which R a and Ra are each independently
  • the present invention also provides according to an embodiment a metal complex according to Formula II:
  • the complex of Formula II comprises a Formula I compound, or a pharmaceutically acceptable salt, tautomer, or ester thereof and a metal (M) selected from the group consisting 10014)
  • the metal is Wm Tc, 1 S6 Re, or l 88 Re.
  • the invention provides a metal complex in which the ratio of the sum of percent injected dose per gram tissue (%ID/g) values for liver and kidney tissues to the %ID/g value for tumor tissue decreases when observed at a first time point, which is one hour post-administration of the metal complex to CA9/293 xenograft mice, and at a second time point, which is four hours post-administration of the metal complex to CA9/293 xenograft mice.
  • the observed decrease in ratio is in the range from a factor of about 2 to a factor of about 4.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one metal complex of a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, or ester thereof; and a pharmaceutically acceptable carrier.
  • a method for imaging a patient suspected of harboring CA IX expressing tumor tissue comprising (a) administering to a patient suspected of harboring CA IX expressing tumor tissue a diagnostically effective amount of a radionuclide metal complex of a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, or ester thereof and (b) obtaining an image of the patient, including any CA IX expressing tumor tissue, if any.
  • kits for the preparation of an agent targeting CA IX expressing tumor tissue comprising a compound according to Formula I.
  • the invention further provides a method for preparing a metal complex for targeting CA IX expressing tumor tissue in a subject by contacting a metal-containing precursor, comprising a metal selected from the group consisting of Pt, Zn, 64 Cu, 186 Re, 188 Re and 99m Tc, with an excess of free, uncomplexed compound of Formula I to provide a mixture comprising: (i) free, uncomplexed compound of Formula I, and (ii) a metal complex thereof.
  • administration of the mixture to a subject suspected of harboring CA IX expressing tumor tissue is done without taking any steps to separate free, uncomplexed compound of Formula I from its metal complex.
  • a poly(carboxyl)amine-containing ligand whose tricarbonyl metal complex, under conditions of a CA IX competitive binding assay (hypoxic assay conditions for the free, unconiplexed ligand by a factor ranging from about 2 to about 200.
  • the ICso value of the tricarbonyl metal complex is lower than that observed under the same assay conditions for the free, unconiplexed ligand by a factor of at least 10, by a factor of at least 20, by a factor of at least 30, by a factor of at least 50, by a factor of at least 1 00,. by a factor of at least 150, or by a factor of at least 200.
  • FIG. 1 illustrates CA IX competitive binding curves for representative compounds and complexes according to Formulae I and II respectively.
  • FIGS 2-6 illustrate tissue biodistribution and bioclearance data for various non- tumor and CA IX expressing tumor tissues.
  • Representative CA IX technitiuni-Wm complexes used in these studies have an ethylene linker connecting the chelator to the sulfonamide moiety.
  • FIGS 5 and 6 illustrate tissue biodistribution and bioclearance data for various non- tumor and CA IX expressing tumor tissues.
  • Representative CA I X technitium-99m complexes used in these studies have an oxybutylene linker connecting the chelator to the sul fonamide moiety.
  • Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 20 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • straight chain alkyl groups include groups such as methyl, ethyl, n -propyl, n-butyl, n-pentyl, n-hexyl.
  • n-heptyl, and n-octyl groups examples include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert- butyl, neopentyl, isopentyl , and 2,2-dimethylpropyl groups.
  • Alkyl groups may be substituted or unsubstituted. Unless the number of carbons is otherwise specified, "lower alkyl” refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.
  • hydroxyalkyl refers to an alkyl group having the indicated number of carbon atoms wherein one or more of the alkyl group's hydrogen atoms is replaced with an - OH group.
  • hydroxyalkyl groups include, but are not limited to, -CH 2 OH, - CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 CH 2 OH,
  • aminoalkyl refers to an alkyl group having the indicated number of carbon atoms wherein one or more of the alkyl group's hydrogen atoms is replaced with an - NR. 1 !? 2 group, wherein R 1 and R 2 each independently refer to hydrogen, unsubstituted (d - Cg)alkyl, unsubstituted aryl and aryl substituted with one to three substituents selected from - halo, unsubstituted alkoxy, thiol and CN.
  • R 1 and R 2 When R 1 and R 2 are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
  • Non-limiting examplars of aminoalkyl groups include, but are not limited to, -CH 2 NH 2 , -CH2CH2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 CH 2 NH 2 , -CH2CH2CH2CH2CH2 NH 2 , and branched versions thereof.
  • alkyl carbonyl denotes an ⁇ ( ( ⁇ s)alkyl-C(0) group in which one or more hydrogen atoms in the Q -Cg alkyl group is replaced with a C(0) group.
  • Representative examples include, but are not limited to, acetyl, propionyl, and CH 3 (CH 2 ) 2 C(0)- group.
  • Carboxyalkylene denotes a divalent -(Ci -C 8 )alkyl group in which one or more hydrogen atoms in the C r C 8 alkyl group is replaced with a C(0) 2 H group.
  • Representative examples include, but are not limited to, -(CH 2 )COOH, or a -CI ! >( ( H? ).iC(( ))- group.
  • halogen refers to -F, -CI, -Br, or -I.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indaeenyl, fluorenyl, phenanthrenyl. triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6- 10 carbon atoms in the ring portions of the groups.
  • Aryl group includes both substituted and unsubstituted aryl groups.
  • Substituted aryl groups may be mono-substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
  • Heteroaryl groups are monocyclic aromatic ring compounds containing 5 or more ring members, or bicyclic aromatic ring compounds containing 6 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups may be substituted or unsubstituted.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthiny
  • heteroatom refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include nitrogen, oxygen, sulfur and phosphorous.
  • amine or amino refers to an -NR a R b group wherein R a and R h each independently refer to a hydrogen, (C
  • -NR a R b is meant to include 1 -pyrrolidinyl, pyridinyl or a 4- morpholinyl ring,
  • amide or “amido” are used interchangeably and are art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula, -C(O) NR a R b group wlierein R,, and R b are as defined above.
  • ligand refers to a species that interacts in some fashion with another species.
  • a ligand may be a Lewis base that is capable of forming a coordinate bond with a Lewis Acid.
  • a ligand is a species, often organic, that forms a coordinate bond with a metal ion.
  • Ligands, when coordinated to a metal ion, may have a variety of binding modes know to those of skill in the art, which include, for example, terminal (i.e., bound to a single metal ion) and bridging (i.e., one atom of the Lewis base bound to more than one metal ion).
  • chelating agent refers to a molecule, often an organic one, and often a Lewis base, having two or more unshared electron pairs available for donation to a metal ion.
  • the metal ion is usually coordinated by two or more electron pairs to the chelating agent.
  • identityate chelating agent tridentate chelating agent
  • tetradentate chelating agent are art-recognized and refer to chelating agents having, respectively, two, three, and four electron pairs readily available for simultaneous donation to a metal ion coordinated by the chelating agent.
  • the electron pairs of a chelating agent forms coordinate bonds with a single metal ion; however, in certain examples, a chelating agent may form coordinate bonds with more than one metal ion, with a variety of binding modes being possible.
  • coordination refers to an interaction in which one multi-electron pair donor coordinatively bonds (is “coordinated") to one metal ion.
  • the term "complex” refers to a compound formed by the union of one or more electron-rich and electron-poor molecules or atoms capable of independent existence with one or more electronically poor molecules or atoms, each of which is also capable of independent existence.
  • poly(carboxyl)amine refers to chemical group that can co-ordinate transition metals.
  • the poly(carboxyl)amine comprises a phenylsulfonamide group that provides binding selectivity to CA IX and which is conjugated via a linker to a metal chelatig group.
  • the metal chelating group usually contains from about 1 to about 10 carboxyl or carboxy(C i -C 6 )alkylene groups as further defined herein. Exemplary of metal chelating groups include the following:
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • 00421 As used herein, the terms “treating” or “treatment” is intended to encompass also diagnosis, prophylaxis, therapy and cure. The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which arc, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each earner must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; ( 10) glycols, such as propylene glycol; (1 1 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; ( 12) esters, such as ethyl oleate and ethyl laurate; ( 13) agar; (14) buffering agents, such as magnesium, magnesium
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 ul ed.; Wiley: New York, 1999).
  • stereoisomer means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example greater than about 90% by weight of one stereoisomer of the compound and less than about 10%o by weight of the other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers f the compound.
  • a "patient” or subject” includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig.
  • the animal can be a mammal such as a non-primate and a primate ⁇ e.g. , monkey and human).
  • a patient is a human, such as a human infant, child, adolescent or adult.
  • the present invention relates to poly(carboxyl)amine-containing ligands and their metal complexes, including radionuclide and non-radionuelide metal complexes, as well as to methods for their synthesis and the use of the inventive complexes in diagnoistic and therapeutic methods, including the radioimaging of tumor tissue, which expresses CA IX, and chemotherapy. More specifically, the present invention relates to a poly(carboxyl)amine- containing compound/ligand according to Formula I, or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.
  • X is selected from the group consisting of ⁇ (CH 2 ) n -, - (CH 2 ) n -0-, - ⁇ CH 2 ) lake-N(R g )-, -(CH 2 ) n -N(R g )-C(0)- and -0-, each R g is hydrogen or (C,-C 6 )alkyl and groups A, B and D are each independently -(CH)-, or -N-.
  • Substituent E is (CH ; )-Z-Q, while E' is (CH ; )-Z-0 ⁇ Group Z is ⁇ (CH 2 ) P -, or - C(O)-.
  • Q is selected from I I, -OR g . or NR a R b and Q' is selected from-H, -OR gi or NR d R e , Substituent groups R a , R b R,i and R,.
  • each are independently hydrogen, (C r C 6 )alkyl, or carboxy(C C 6 )alkylene, while substituent G is -(CH(R m )) n -R h -, or -(CH 2 ) p -C(0)-R h .
  • Group R h in Formula I is ⁇ H, -OH, NR a R b , or C0 2 I I, while R m is I I, -COOH, - COO(Ci-C 6 )alkyl.
  • Subscripts m, n and p independently are integers between 0 to 10 inclusive and Formula 1 provides for aromatic or non-aromatic compounds by representing the option of having one or more double bonds using the symbol ⁇ - ' .
  • any alkyl, heteroaryl, amine, or carboxyalkyl can be optionally substituted with one or more members selected from the group consisting of hydrogen, carboxy(C C 6 )alkylene, hydroxy(C r C 6 )alkylene and amino(C C 6 )alkylene,
  • substituent groups R a and R b are each independently
  • R e (C) -C(,)alkyl for example, an alkyl group that is further substituted with carboxyalkylene groups.
  • exemplary of such a Formula I compound is one in which R a and R ⁇ j are each independently
  • compounds according to Formula I are inhibitors of the enzyme Ca IX.
  • Complexes of a Formula I compound with radionuclides therefore, are candidate radioimaging agents for detecting and monitoring the progression of cancers.
  • Exemplary poly(carboxyl)amine-containing Fomiula I compounds include without limitation those illustrated in Table 1 .
  • the present invention is also directed to the synthesis and use of metal complexes of poly(carboxyl)amine-containing Formula 1 compounds.
  • metal complexes that conform to Formula II are provided, including radionuclide and non-radionuclide metal complexes.
  • X is selected from the group consisting of- (CH 2 ) lake-, -(CH 2 ) n -0-, - ⁇ CH2) n -N(R B )-, -(CH 2 ) n -N(Rg)-C(0)- and ( ) -.
  • each R g is hydrogen or (Ci -C ( ,)alkyl and groups A, B and D are each independently (CH)-, or -N-.
  • Substituent E is (CH 2 )-Z-Q, while E' is -iCH 2 )-Z-Q' .
  • Group 2 is -(CH 2 ) P -, or - C(O)-.
  • Q is selected from-FI, -OR g , or NR a R h and Q' is selected from-H, -OR g , or NRr f l ⁇ ..
  • Group R h in Formula II is-H, -OFl, NR a R b , or -CO2H, while R m is-H, -COOH, - COO(C C 6 )alkyl .
  • Subscripts m, n and p independently are integers between 0 to 10 inclusive.
  • Formula II also provides for aromatic or non-aromatic compounds by providing the option of having one or more double bonds using the symbol ⁇ - M can be any radionuclide or non-radionuclide metal, preferably, rhenium- 1 86, rhenium- 188, copper-64, technetium-99m, platinum, manganese, zinc and the like.
  • any alkyl, hcteroaryl, amine, or earboxyalkyl can be optionally substituted with one or more members selected from the group consisting of hydrogen, earboxy(C C 6 )alkylene, ydroxy(C r C 6 )alkylene and amino(Ci-C 6 )aIkylene.
  • Exemplary Formula II complexes include without limitation those illustrated in Table 2.
  • the present invention provides a method of preparing an imaging or therapeutic agent for targeting CA IX expressing tumor tissue using a Formula II complex.
  • the inventive method comprises contacting a metal selected from the group consisting of Pt, Zn, M Cu, ""'Re, 188 Re and Wm Tc with excess of a compound according to Formula 1 using a pharmaceutically acceptable carrier, to provide a mixture that comprises the desired Formula II metal complex as well as quantities of the corresponding free, uncomplexed Formula I compound.
  • the percent amount of the metal-complexed Formula I compound in the reaction mixture is from about 0.01 % to about 100%.
  • the inventive method for of preparing an imaging agent for targeting CA IX expressing tumor tissue provides a mixture that has from about 0.01 % to about 90%, from about 0.01 %) to about 80%, from about 0.01 % to about 60%, from about 0.01 % to about 50%, from about 0.01 % to about 40%, from about 0.01 %) to about 30%, from about 0.01 % to about 20%, from about 0.01 % to about 10%, from about 0.01 % to about 5%, from about 0.01 % to about 1 .0% of the metal-complexed Formula I compound.
  • Formula I compounds synthesized and tested Formula I compounds (and contemplate additional variations) (a) to investigate the group) in modulating CA IX inhibition; (b) to investigate the role of the type (chemical nature) of radionuclide chelator groups in modulating CA IX inhibition; and (c) to investigate the role of the chemical nature of the linker that separates the radionuclide chelator group from the sulfonamide group.
  • HeLa cells 9.3 nM (HeLa cells)
  • the inventive therapeutic or imaging agent will be provided to a physician or a qualified licensed medical practitioner in the form of a kit that will contain a Formula I compound its pharmaceutically acceptable salt, tautomer or ester.
  • the compound can be in the form a dry lyophilized powder that is appropriately packaged, or can be provided in a sealed sterile vial that is opened prior to administration to a patient in need.
  • the kit will contain an inventive therapeutic or imaging agent that has been dissolved in a suitable pharmaceutically acceptable earner and is provided as a solution in a sealed sterile vial or scored ampule.
  • Formula I compound is provided as a powder or in solution form, it optionally can contain other pharmaceutically acceptable reagents such as sodium boranocarbonate, sodium carbonate, sodium tartarate and sodium borate that help stabilize, buffer and increase the shelf life of the Formula I compounds.
  • other pharmaceutically acceptable reagents such as sodium boranocarbonate, sodium carbonate, sodium tartarate and sodium borate that help stabilize, buffer and increase the shelf life of the Formula I compounds.
  • inventive therapeutic or imaging agent When the inventive therapeutic or imaging agent is provided as a dry lyophilized powder, the medical practitioner will reconstitute the powder in an appropriate volume of a pharmaceutically acceptable solvent at the site of administration. Whatever the form of the inventive Formula I compound in the kit, a solution of this compound is combined with an appropriate radionuclide precursor prior to administration to the patient.
  • dichloromethane DCM
  • ethyl acetate EA
  • hexancs Hex
  • dichlorocthane DCE
  • dimethyl formamide DMF
  • trifluoroacetic acid TEA
  • tetrahydrofuran THF
  • carbonyldiimidazole GDI
  • DCC dicyclohexyl carbodiimide
  • DMAP dimethylaminopyridine
  • BOC diisopropylethyl amine
  • TEA triethylamine
  • CBZ ethanol
  • EtOH methanol
  • [ 4m Tc(CO) 3 (H 2 0) 3 f was prepared using the Isolink® radiolabeling kits by the methods published in the literature Sodium Pertechnetate, 7400 MBq (2()0mCi), in saline (2.5 ml.) was added to an Isolink® radiolabeling kit and the vial was placed in an oil bath at 100 C. The reaction was heated for 45 minutes and IN HC1 (200 ⁇ was then added to neutralize the reaction mixture. The product, [' )9m Tc(CO)3(H 2 0) .
  • Step 3 tetra-tert-butyl 4,4'-((2,2'-(2,2'-(((4- sulfamoylphenethyl)azanediyl)bis(methylene)) bis( l H-imidazole-2, 1- diyl))bis(acetyl))bis(azancdiyl))bis(4-(3-(tert-butuxy)-3-oxopropyl)heplancdioate
  • Step 4 Re(CO) l
  • Step 4 [Re(CO) 3 ] [ 2,2',2",2"'-((2,2 , -(2,2'-(((4-(4-sulfamoylphenoxy)butyl)azanediyI) bis(methyIene))bis(lH-imidazole-2,l-diyI))bis(acetyI))bis(azanetriyI))tetraacetic acid] (Re-(12))
  • Step 1 di-tert-butyl 2,2'-((2-(2-(((4-sulfamoylphenethyl)aniin )methyl)- l H-imidazol- 1 - yl)acetyl)azanediyl)diacetate
  • Step 2 di-tert-butyl 4-(2-(2-((((l -(2-(bis(2-(tei t-butoxy)-2-oxoeth l)aniino)-2-oxoethyl)- l H-imidazol-2-yI)methyl)(4-suIfanioyIphenethyl)amino)methyl)-l H-imidazol-l- yl)acetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate
  • Step 3 Re(C())3 ⁇ 4
  • Step 1 tetra-tert-butyl 4,4'-((2,2'-(2,2'-(((4-(4-sulfanioylphenoxy)butyI)azaiiediyI) bis(methyIene))bis(lH-imidazoIe-2,l-diyl))bis(acetyI))bis(azanediyI))bis(4-(3-(tert- butoxy)-3-oxopropyl)heptanedioate
  • Step 1 tetra-tert-butyl 4,4'-((2,2'-(2,2'-(((3-(4-sulfamoylphenyl)propyI)azanediyl) bis(methylene))bis(lH-imidazole-2,l-diyl))bis(acetyl))bis(azanediyl))bis(4-(3-(tert- butoxy)-3-oxopropyI)heptanedioate
  • Step 3 tetra-tert-butyl 4,4'-((2,2'-(2,2'-(((6-(4-sulfamoylphenoxy)hexyl)a/anediyl) bis(methylene))bis(l H-imidazole-2, l-diy]))bis(acetyl))bis(azanediyl))bis(4-(3-(tert- butoxy)-3-oxopropyI)heptanedioate
  • reaction mixture was cooled to 0 °C, and treated with NaBH(OAc) 3 (0.422 g). The reaction mixture was stirred at room temperature for overnight and decomposed with water. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by biotage over silica gel to afford the desired product ( 1 53 mg). MS (ESI), 672.4 (M/2+H) + .
  • Step 1 tetra-tert-butyl 2,2',2",2"'-((2,2'-((3-hydroxypropyl)azanediyl)
  • Step 3 tetra-tert-butyl 2,2',2 , , ,2'"-((2,2'-((3-(2-forniyl- l H-imidazol- l - yl)propyl)azanediyI)bis(acetyI))bis(azanetriyI))tetraacetate
  • Step 4 octa-tert-but l 2,2 , ,2",2” , ,2” , ,2 M “ , ,2” M “,2””” , -((2,2',2",2'"-(((2,2 , -(((4- suIfamoylphcnclhyI)azancdiyl)bis(nicthylcne))his( 1 H-imidazole-2, 1 -diyl))-bis(pr pane- 3, l-diyl))bis(azanctriyI))tetrakis(acetyl))tetrakis(azanetriy ))-octaacctate
  • reaction mixture was cooled to 0 °C, and treated with NaBH(OAc) 3 (0.254 g, 1.2 mmol). The reaction mixture was stirred at room temperature for overnight and decomposed with water. The reaction mixture was extracted with DCM. The organic layer was dried and concentrated under reduced pressure. The residue was purified by biotage over silica gel to afford the desired product (237 mg). MS (ESI), 808.5 (M/2+H) + . Step 5.
  • Step 1 di-tert-butyl 2,2'-(4,4'-(((4-sulfanioyIphenethy )a/anediyl)bis(methylcne))bis( l I I- 1 ,2, -tria/ole-4, 1 -diy l))diacetate (M I P- 1479)
  • Step 1 (2S,2 'S)-tetra-tert-butyl 2,2'-(4,4'-(((4-sulfamoylphcnethyl)azanediyI) bis(mcthylenc))bis( 1 H- 1 ,2,3-triazole-4, l-diyl))dipentanedioate
  • Step 1 di-tert-butyl 2,2'-((2-(2-(((4-sulfamoylphenethyl)amino)methyl)- l 11-iniida/ol- l - yl) acetyl) azancdiyl)diacetate
  • reaction mixture was concentrated under reduced pressure to give a residue.
  • residue was purified by biotage over silica gel to afford di-tert-butyl 2,2'-((2-(2-(((4- sulfamoylphenethyl)amino)methyl)- l H-imidazol-l -yl)acetyl)azanediyl)diacetate as a white solid (547 mg, 24%).
  • Step 3 di-tert-butyl 2,2'-((2-(2-((((( l -(2-((3-i(ui(iplicnyl)amin )-2-oxoethyl)- l H-iniidazol-
  • the reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for overnight and decomposed with water.
  • the reaction mixture was extracted with DCM.
  • the organic layer was dried and concentrated under reduced pressure.
  • the residue was purified by biotage over silica gel eluting with DCM to 40% MeOH in DCM to afford di-tert-butyl 2,2'-((2-(2-(((( l -(2-((3-iodophenyl)amino)-2- oxoethyl)-l H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)methyl)-l H-imidazol- 1 - yl)acetyl)azanediyl)diacetate (254 mg, 56%).
  • Step 4 2,2'-((2-(2-(((((l-(2-((3-iodophcnyl)amin )-2-oxoethyi)-l H-imida/ol-2- yl)methyI)(4-sulfamoyIpheiiethyl)amino)mcthyl)-l H-imidazol-l- yl)acetyl)a/anediyl)diacetic acid ( 18)
  • Step 2 di-tert-butyl 2,2'-((2-(2-(((4-iodobenzyI)(4-suIfamoyIphenethyI)amino)methyl)- 1 H-imidazol- l -yl)acetyl)azanediyl)diaeetate
  • Step 1 tert-butyl 2-(2-(((4-iodobenzyI)(4-siiIfamoylphenethyl)amino)methyl)-lH- iniida/ol- 1 -yl)acetate
  • the human cervical cancer cell line, Hel .a was obtained from the American Type Culture Collection (Rockville, MD).
  • the human renal cancer cell lines, SK-RC-52 which constitutively expresses CA IX, and SK-RC-59 which does not express CA IX, were obtained from Memorial Sloan Kettering Cancer Center. All cells were grown according to the supplier's protocols in a humidified incubator at 37 °C/5% C0 2 . Cells were removed from flasks for passage or for transfer to 12-well assay plates by incubating them with 0.25% trypsin FDTA ( lnvitrogen).
  • the assay media was then removed and the cells were washed 2x with cold HBSS/0.5% BSA, collected by adding 0.25 mL of 1 % SDS, and transferred to a 1 .5 mL tube for counting the amount of radioactivity bound using a Wallac 1282 automated gamma counter.
  • IC 5 o values were determined by non-linear regression using GraphPad Prism software.
  • the radionuclide complexes of compounds that conform to Formula I are more potent inhibitors of CA IX with IC50 values in the nanomolar range.
  • the free (uncomplexed) compounds bind CA IX with IC50 values that are at least 2-250-fold greater than the IC50 of the corresponding complex
  • complexes according to Formula II bind CA IX at least 2-200-fold more tightly than the corresponding free, uncomplexed compounds.
  • the binding, or inhibitory potency of the metal complex is at least 2-200-fold, 2- 175-fold, 2- 150-fold, 2- 125-fold, 2- 100-fold, 2-90- fold, 2-80-fold, 2-70-fold, 2-60-fold, 2-50-fold, 2-40-fold, 2-30-fold, 2-20-fold,or 2-10-fold greater than the binding, or inhibitory potency of the corresponding free (uncomplexed) compounds.
  • rhenium and technetium tricarbonyl metal complexes of certain Formula I compounds competitively bind more tightly (lower inhibition constants (IC50) values), to CA IX expressing hypoxic HeLa cells than the coiTesponding free, uncomplexed Formula 1 compounds (ligands).
  • the observed IC50 values for the tricarbonyl metal complex is lower than the observed IC50 value for free, uncomplexed ligand by a factor of at least 10, by a factor of at least 20, by a factor of at least 30, by a factor of at least 50, by a factor of at least 100, by a factor of at least 1 50, or by a factor of at least 200.
  • the tricarbonyl metal complexes of Formula I compounds are suitable candidate agents for imaging tumor tissues that are known to have a high expression of CA IX as compared to non-tumor tissues, as
  • mice Prior to inoculation of mice, Hek293/CA9 cells were trypsinized, counted, and suspended in 50 % PBS with I mg/ml D-glucose, 36 mg/ml sodium pyruvate, 50% Matrigel (BD Biosciences, Franklin Lakes, NJ), NCr nu ilu mice were anesthetized by intraperitoneal injection of 0.5 ml Avertin (20 mg/ml) (Sigma-Aldrich) and then inoculated subcutaneously into the hind flank with 2 x 1 0 6 cells suspended in 0.25 ml of buffer.
  • Avertin 20 mg/ml
  • the distribution of the inventive CA IX inhibitors was measured in the following tissues: tumor, blood, heart, liver, lungs, spleen, large and small intestine, stomach, kidneys and skeletal muscle. Tissues were excised from euthanized mice at the predetermined time point following administration of the inventive CA IX inhibitors. The tissues were weighed (wet), transferred to plastic tubes and the radioactivity counted using an automated ⁇ -counter ( 1 KB Model 1282). The percent radioactivity remaining in a tissue at a specific time interval post administration of the inventive CA IX was expressed as percent injected dose per gram tissue (%ID/g) and percent injected dose per organ (%DPO). Graphically, data from such studies involving different inventive CA IX inhibitors are shown in Figures 2-6.
  • Figures 2-6 illustrate the in vivo biodistribution characteristics and pharmacokinetic behavior of certain metal complexes of poly(carboxyl)amine-containing ligands that conform to Formula I as described herein.
  • J 0133 J Data presented in Figures 2-4 also illustrate a correlation between the number of carboxyl groups that are present in the complex and the pharmacokinetic profile (tissue distribution and clearence) for technicium-99m complexes of certain Formula I compounds.
  • the complex illustrated in Figure 2 has two methylene carboxyl groups per immidazole chelating group, for a total of four methylene carboxyl groups in the molecule [ 99m Tc]-(5) .
  • the complex illustrated in Figure 3 has a total of five methylene carboxyl groups, while the complex of Figure 4 has a total of six methylene carboxyl groups.
  • CA IX inhibitors according to the present invention can be detected in various tissues tested in this study.
  • high concentrations of CA IX inhibitors according to the present invention were detected in the kidney and liver of mice.
  • the present inventors believe that the greater concentration o f CA IX inhibitor in kidney and liver are primarily due to the role of these two organs in detoxification of drugs and their excretion from the body.
  • the presence and number of carboxyl groups may also have an effect on the tissue distribution and bioclearance of the inventive CA IX inhibiotors. For instance, at a time interval of one hour post administration of the inventive CA IX inhibitors the %ID/g of tumor tissues remained constant at a measured value of approximately 10% for each of the three CA IX inhibitors tested. In contrast, the %ID/g of liver decreased from a value of 20% for the CA IX inhibitor having a total of four methylene carboxyl groups ( Figure 2), to a value of 5% and 2% in the livers obtained from mice treated with the CA IX inhibitor having a total of five and six methylene carboxyl groups respectively ( Figure 3 and 4 respectively).
  • Figure 3 which illustrates the pharmacokinetic behavior of a compound of Formula I having five carboxyl groups, shows that this ratio decreases by a factor of about 3.9.
  • Figures 4 and 6 in which the compound of interest possesses six carbo yl groups, shows that this ratio decreases by a factor of about 4.0.
  • the metal complexes thereof appear to retain a high value for the percent injected dose per gram tissue (%ID/g) in the target tissue, which is CA IX expressing tumor tissue, over the course of the first four hours post-administration.

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Abstract

La présente invention concerne des inhibiteurs de CA I X qui se conforment à la Formule 1 dans laquelle les substituants X, A, B, D, E, E' et G sont tels que définis ci-dessus. L'invention concerne également des complexes métalliques Pt, 64Cu, 186Re, 188Re et 99mTc de composés de Formule 1 qui peuvent être utilisés comme agents candidats pour l'imagerie de tumeurs.
EP13733617.8A 2012-01-06 2013-01-04 Complexe métalliques de poly (carboxyl) amine contenant des ligands ayant une affinité pour l'anhydrase carbonique ix Withdrawn EP2800471A4 (fr)

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US20130216477A1 (en) 2013-08-22
US9120837B2 (en) 2015-09-01
CA2860504A1 (fr) 2013-07-11
US20160009664A1 (en) 2016-01-14
US9422251B2 (en) 2016-08-23
AU2013207486A1 (en) 2014-08-21
WO2013103813A1 (fr) 2013-07-11

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